Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with Mantle Cell Lymphoma (MCL) who have received prior therapy, Chronic Lymphocytic Leukemia (CLL) who have received prior therapy and CLL with the 17p deletion geneticmutation (del 17p).
CN101610676A discloses that 4-phenoxybenzoic acid as a starting material was chlorinated, condensed with malononitrile and then cyclized with anhydrous hydrazine to give a pyrazole intermediate, which was then cyclized with formamide to give 4-aminopyrazolo[3,4-d]pyrimidine core, and condensed with a chiral alcohol via Mitsunobu reaction followed by the removal of the protecting group Boc and acrylation to afford a product. This synthetic route is shown as follows:

The above synthesis route is lengthy, and involves many steps. The yield in the Mitsunobu reaction step is low (34%), and the total yield is only 8.1%. Triphenylphosphine resin as an expensive and unavailable reagent is used, and purification through chromatography is finally needed to obtain ibrutinib, resulting in a high industrialization cost and complex operations.
CN103121999A discloses that 3-bromo-4-aminopyrazolo[3,4-d]pyrimidine as a starting material was coupled to 4-phenoxybenzeneboronic acid via Suzuki reaction, condensed with a chiral alcohol in the presence of cesium carbonate as a base, protected with trifluoroacetyl group, deprotected to remove the protecting group Boc, acrylated, and then deprotected to remove the protecting group trifluoroacetyl to afford ibrutinib. This synthetic route is shown as follows:

This synthesis route is also lengthy; the Suzuki reaction using PdCl2(PhCN)2 as a catalyst is difficult to be repeated and a large amount of the catalyst is required; it takes 24 hours to carry out the condensation step using cesium carbonate as a base, and therefore the reaction time is too long; and the steps for protection and deprotection of amino group prolong this reaction route and reduce the total yield, which was 21.5% (with 3-bromo-4-aminopyrazolo[3,4-d]pyrimidine as the starting material). Therefore, this process is not suitable for a large-scale industrial production.
WO2014022390A1 reports that 4-aminopyrazolo[3,4-d]pyrimidine as a starting material was iodinated to prepare intermediate 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, which was then coupled to 4-phenoxybenzeneboronic acid via Suzuki reaction, condensed with a chiral alcohol via Mitsunobu reaction, deprotected with hydrochloric acid to remove the protecting group Boc and form a salt, and finally acrylated to afford ibrutinib. This synthetic route is shown as follows:

A large amount of catalyst tetraphenylphenylphosphine palladium is used in the Suzuki reaction in this synthesis route, and the reaction time is up to 24 hours; it takes a long time to carry out the Mitsunobu reaction, and its yield is low (38%); the total yield of this synthesis route is only 9.3%: and purification by chromatography is required. Therefore, this route is not suitable for industrial production, either.
In addition, commercially available acryloylchloride generally contain 1% to 3% of 3-chloropropionyl chloride, which results in the presence of 3-chloropropionylated impurities in the product ibrutinib, making the purification and industrial application difficult.